Propylphosphonic anhydride (BOP-Cl) (CAS#68641-49-6)
The substance identified by CAS# 68641-49-6 is bis(2-oxo-3-oxazolidinyl)phosphinic chloride, universally abbreviated as BOP-Cl. While the query uses the name “Propylphosphonic anhydride” (T3P®), T3P corresponds to a different CAS registry number; BOP-Cl is chemically distinct and is the correct identity for this CAS number. BOP-Cl is a phosphinic chloride bearing two oxazolidin-2-one rings attached to a central phosphorus atom that also carries a chlorine substituent. It is supplied as a white to off-white crystalline powder with a melting point of approximately 191 °C (with decomposition) and a predicted density of 1.71 g/cm³. The compound is moisture-sensitive and must be stored under an inert gas in a cool, dark place, preferably below 15 °C, to prevent hydrolytic degradation of the reactive P–Cl bond.
The reactivity of BOP-Cl centers on the phosphinic chloride group, which is highly electrophilic and readily reacts with carboxylic acids to form an activated acyloxyphosphonium intermediate. This intermediate is sufficiently reactive to undergo nucleophilic attack by amines—including sterically hindered amines that fail with carbodiimide-based coupling reagents—to form amide bonds under mild conditions. The oxazolidinone leaving groups are water-soluble, which simplifies work-up and contributes to the reagent’s utility in solution-phase and solid-phase peptide synthesis.
Applications
The principal application of BOP-Cl is as a peptide coupling reagent and carboxylic acid activator in peptide and amide synthesis. It is particularly valued for its ability to mediate coupling with sterically hindered amines and amino acids—substrates that are poorly reactive or completely unreactive with conventional carbodiimide reagents such as DCC or EDC. The reagent is used in both solution-phase peptide synthesis and solid-phase peptide synthesis (SPPS) , and has been applied in the construction of complex peptide sequences where standard coupling methods fail.
Beyond peptide chemistry, BOP-Cl serves as a general condensation reagent for amide bond formation in medicinal chemistry and process development. It activates carboxylic acids toward reaction with a broad range of amine nucleophiles, enabling the preparation of amides, dipeptides, and peptidomimetic scaffolds. The reagent is also employed in the synthesis of β-lactams, heterocycles, and other pharmaceutically relevant intermediates where mild activation of a carboxylic acid is required. Its use extends to the esterification and thioesterification of carboxylic acids under appropriate conditions, although amide formation remains the dominant transformation. BOP-Cl is compatible with standard Fmoc- and Boc-based protecting group strategies and is typically used in the presence of a tertiary amine base such as triethylamine or DIPEA in solvents including dichloromethane, DMF, or acetonitrile.
Preparation Method
BOP-Cl is prepared by the reaction of 2-oxazolidinone with a phosphorus chloride source. Two principal routes are documented.
In the phosphorus oxychloride (POCl₃) route, 2-oxazolidinone is reacted with POCl₃ to install the phosphinic chloride core with two oxazolidinone substituents. The reaction is typically conducted under anhydrous conditions to preserve the reactive P–Cl bond, and the product is isolated by filtration or precipitation and purified by recrystallization.
In the phosphorus pentachloride (PCl₅) route, PCl₅ is added in one portion to a solution of 2-oxazolidinone in nitromethane. A representative procedure uses 41.6 g (200 mmol) of PCl₅ and 34.8 g (400 mmol) of 2-oxazolidinone in 380 mL of nitromethane; the mixture is stirred at 20–25 °C for 4 hours and then at 40–45 °C for an additional hour to drive the reaction to completion. The product is isolated after work-up and purified to the required specification.
Safety Information
BOP-Cl is classified under GHS with the signal word Danger. The core hazard statements are H314 (Causes severe skin burns and eye damage) and H290 (May be corrosive to metals). Some supplier classifications additionally list H302 + H312 + H332 (Harmful if swallowed, in contact with skin, or if inhaled) , reflecting moderate acute toxicity by multiple routes. The substance is assigned to Skin Corrosion Category 1 and is a serious eye damage hazard. It is corrosive to metals and should be stored in compatible containers. BOP-Cl is moisture-sensitive and reacts with water, releasing hydrogen chloride and heat; this reactivity adds to the inhalation and corrosion hazards in the presence of moisture.
For safe handling, all manipulations should be performed in a well-ventilated fume hood with local exhaust ventilation. Personal protective equipment must include chemical splash goggles and a face shield, corrosion-resistant gloves, protective clothing, and respiratory protection where dust or acid vapors may be generated. In case of skin contact, remove contaminated clothing immediately and rinse the skin with copious water; for eye contact, rinse cautiously with water for several minutes and seek immediate medical attention. If inhaled, move to fresh air and seek medical attention if symptoms persist. Do not induce vomiting if swallowed; rinse the mouth and seek urgent medical care. BOP-Cl should be stored in a cool, dark, dry place under inert gas, with containers kept tightly closed and protected from moisture and incompatible materials such as strong oxidizers and strong bases. The transportation classification is UN 3261, Class 8, Packing Group II; release to the environment should be avoided, and spills should be cleaned up with inert absorbent and disposed of in accordance with local regulations.
